Temporal transcriptomic changes during neurodevelopment in a mouse model of Smith-Lemli-Opitz syndrome.

Abstract

Smith-Lemli-Opitz syndrome (SLOS) is a cholesterol biosynthesis disorder caused by mutations in the DHCR7 gene, leading to reduced cholesterol production and accumulation of its precursor, 7-dehydrocholesterol. SLOS displays a wide range of neurodevelopmental defects, intellectual disability, and behavioral problems. However, an in-depth study of the temporal changes in gene expression in developing brains has not been conducted before. In this work, we carried out the transcriptomic analysis of whole brains from WT and Dhcr7-KO mice at embryonic day 12.5 (E12.5), E14.5, E16.5, and postnatal day 0 (PND0). First, we observed the expected downregulation of the Dhcr7 gene in the Dhcr7-KO brains, as well as changes in other genes involved in cholesterol biosynthesis at all time points. Pathway and GO term enrichment analyses revealed affected signaling pathways and biological processes that were shared amongst time points and unique to individual time points. Specifically, pathways important for embryonic and neural development, including Hippo, Wnt, and TGF-β signaling pathways, are most significantly affected at the earliest time point, E12.5. Additionally, neurogenesis-related GO terms were enriched at earlier time points, consistent with the timing of development. Conversely, pathways related to synaptogenesis, which occur later in development than neurogenesis, are significantly affected at the later time points, E16.5 and PND0, including cholinergic, glutamatergic, and GABAergic synapses. In vitro neurogenesis experiments using GABAergic neuronal precursors isolated from embryonic mouse brain confirmed that loss of Dhcr7 led to decreased proliferation and premature neurogenesis, consistent with the transcriptomic changes.